Glaucoma is a disease of the eye that is characterized by an elevation in intraocular pressure. The elevation in pressure results from an impairment in the outflow of aqueous humor from the anterior chamber of the eye via the trabecular meshwork (see Tripathi et al, Drug Develop. Res. 27:191 (1992)). Treatments for glaucoma focus on decreasing intraocular pressure and thereby avoiding damage to the optic nerve. Left untreated, glaucoma can lead to blindness.
Numerous agents have been used for the treatment of glaucoma, however, many are accompanied by undesirable side effects, such as ocular pain and localized allergy. Examples of such agents include adrenergic amine, epinephrine, and cholinesterase inhibitors. Although topical application is typically used, absorption of at least certain of these compounds can result in adverse systemic effects including headaches, nausea and the like.
U.S. Pat. No. 4,757,089 discloses a treatment for glaucoma that involves the administration to the eye of ethacrynic acid or analogs thereof that react with sulfhydryl groups of the trabecular meshwork of the eye. Erickson-Lamy et al (Invest. Opthalmol. Vis. Sci. 33:2631 (1992)) have reported that ethacrynic acid, acting via a SH-reactive mechanism, induces cytoskeletal changes that result in the observed physiologic effects on outflow facility. WO 92/16199 discloses an improvement in the method described in U.S. Pat. No. 4,757,089 that involves the use of agents that mask the sulfhydryl reactive site as the drug passes into the eye. The masking agent dissociates in the eye thereby freeing the sulfhydryl reactive site for interaction with the trabecular meshwork. Use of such masking agents prevents side effects (such as corneal edema) that occur in the absence of the masks. (See also Epstein et al, Current Eye Res. 11:253 (1992).)
The present invention provides a further approach to glaucoma treatment. The present method involves the use of compounds that increase aqueous humor outflow but are non-SH reactive. The mechanism of action of the present compounds would thus appear to be distinct from that of ethacrynic acid and the analogs thereof disclosed in U.S. Pat. No. 4,757,089 and WO 92/16199.